Obesity and Type 2 diabetes occurs with an alarming incidence in the United States, altogether affecting more than 120 million people, many of which are children. Currently, more people are obese and have diabetes in the world as compared to the number of humans who are undernourished. These diseases are associated with billions of dollars in health costs each year. The cause of common obesity/diabetes is unknown and effective treatments do not exist. Leptin is a hormone that is normally produced in fat tissue, released into circulation, and acts in the brain to reduce caloric intake and bodyweight, and to improve glucose balance. Among many leptin-responsive cells in the brain are two neuronal populations, the hypothalamic proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons. POMC produce peptides that act via specific melanocortin receptors in the brain to reduce food intake and body weight, and their expression is stimulated by leptin. In parallel, leptin inhibits expression and release of AgRP, a peptide that increases caloric intake by inhibiting POMC-peptide signaling. Humans and mice lacking leptin or leptin receptors, or have mutations in the POMC or the melanocortin receptor genes, suffer from severe hyperphagia, obesity, and insulin resistance. We will in this proposal use transgenic mice to investigate how leptin decreases caloric intake and reduces body weight, and vastly improves glucose balance, by acting via POMC and AgRP neurons. Altogether, the proposed studies will increase our understanding of how leptin acts to decrease body weight and food intake, and to improve glucose balance. The findings may help identification of novel anti-obesity/diabetes drug-targets. PUBLIC HEALTH RELEVANCE: This project aims to identify mechanisms whereby the hormone leptin acts in the brain to reduce body weight and fat mass, reduce caloric intake, and improve glucose metabolism. Specifically, we will identify pathways by which leptin influences these processes, via signaling in hypothalamic POMC and AGRP neurons. The grant will also determine regulation of leptin receptor localization within these specific neurons as this pertains to mechanisms of leptin-resistant obesity. Obtained data will therefore be relevant for future identification of novel anti-obesity/diabetes drug pathways/targets.